Question

Humanized monoclonal antibodies are a combination of

• A. Heavy and light chain constant domains are from human and variable from mouse
• B. Heavy chain constant domain from mouse and light chain constant domain from human
• C. Heavy and light chain constant domains and variable from mouse
• D. Heavy and light chain constant domains are from mouse and variable from human

Hint:

• Murine mAb All mouse.
• Chimeric mAb Mouse Variable regions + Human Constant regions.
• Humanized mAb Mostly Human Variable region frameworks + Mouse CDRs + Human Constant regions. (Minimizes mouse content to just the essential antigen-binding loops).
• Fully Human mAb Entirely human sequences.
• The goal of humanization is to reduce immunogenicity while retaining antigen-binding specificity.

Answer 1

The Correct Option is A

Monoclonal antibodies (mAbs) produced entirely from non-human sources (e.g., mouse) can elicit an immune response (HAMA - Human Anti-Mouse Antibody response) when administered to humans, reducing their efficacy and potentially causing side effects. To overcome this, various types of engineered antibodies have been developed:

• Chimeric Antibodies: Combine the variable regions (which bind to the antigen) of a mouse antibody with the constant regions of a human antibody. (~60-70% human).
• Humanized Antibodies: These are more extensively "humanized." They typically consist of the constant regions from a human antibody, and only the Complementarity Determining Regions (CDRs) – the hypervariable loops within the variable regions that are directly involved in antigen binding – are derived from the mouse antibody. The framework regions (FRs) of the variable domains are also of human origin or modified to be more human-like. (~90-95% human).
• Fully Human Antibodies: Produced using transgenic mice engineered to produce human antibodies, or by phage display technologies.

The question asks about "Humanized monoclonal antibodies."
Option (a) states: "Heavy and light chain constant domains are from human and variable [domains] from mouse". This is a description more aligned with chimeric antibodies or a simplified view of humanized antibodies where the entire variable region is from mouse. However, for "humanized," usually only the CDRs are mouse-derived, grafted onto human variable region frameworks, and then combined with human constant regions.

Let's re-evaluate options based on the most common understanding of "humanized": The variable domains (\( V_H \) and \( V_L \)) are responsible for antigen binding. The constant domains (\( C_H \) and \( C_L \)) determine the antibody's effector functions and are major contributors to immunogenicity if foreign.

In humanized antibodies, the aim is to make them mostly human. This means:

• Constant domains (Fc region, parts of Fab) are human.
• Variable domains: The antigen-binding specificity comes from the mouse (or other non-human) antibody. So, the critical parts of the variable domains (the CDRs) are from mouse, grafted onto human variable domain frameworks.

Option (a) "Heavy and light chain constant domains are from human and variable from mouse" implies the entire variable regions (\( V_H \) and \( V_L \)) are from mouse. This is closer to chimeric, but sometimes "humanized" is used more broadly if significant parts of variable regions are human frameworks.
Option (c) "Heavy and light chain constant domains and variable from mouse" - this is even more mouse content.
Option (d) "...constant domains are from mouse and variable from human" - this is the opposite of humanization.

Considering the simplification in MCQs, option (a) is the best fit. It correctly identifies human constant domains and mouse variable (antigen-binding) domains.
The key is that the constant regions are human to reduce immunogenicity, and the antigen-binding parts (variable regions or just CDRs) are from the non-human source.

Heavy and light chain constant domains are from human and variable from mouse